Interstitial deletions of the distal short arm of chromosome 2 including MYCN have only been reported for a small number of individuals. Germline deletions and mutations of MYCN cause Feingold ...syndrome 1 (FS1), a rare disorder characterized by microcephaly, digit anomalies, gastrointestinal atresias, short stature, dysmorphic features, and intellectual disability. We present a series of six individuals referred for SNP microarray with overlapping deletions of 2p ranging from 3.4 to 16.8 Mb in size, with a common overlapping region of 1.53 Mb spanning (14,614,477–16,148,021) hg19 and including five genes: NBAS, DDX1, MYCNUT, MYCNOS, and MYCN. Clinical information was available for five individuals. Clinical features included core features of FS1 such as microcephaly, digit anomalies, and gastrointestinal atresias as well as structural cardiac defects, hearing loss, and renal anomalies, which are features less consistently associated with FS1. Other features observed in several individuals, that have not specifically been associated with FS1 were motor delay, structural brain abnormalities, genital abnormalities, and radioulnar synostosis. These results indicate that while individuals with deletions of 2p spanning several megabases and including MYCN can present with features not typically associated with FS1, the common core features are usually present.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Steroidogenic factor 1 (SF1) is a nuclear receptor encoded by the NR5A1 gene. SF1 affects both sexual and adrenal development through the regulation of target gene expression. Genotypic male ...and female SF1 knockout mice have adrenal and gonadal agenesis with persistent Müllerian structures and early lethality. There have been several reports of NR5A1 mutations in individuals with 46,XY complete gonadal dysgenesis (CGD) or other disorders of sex development (DSD) with or without an adrenal phenotype. To date microdeletions involving NR5A1 have been reported in only two patients with DSDs. We report a novel microdeletion encompassing NR5A1 in a patient with 46,XY DSD and developmental delay. The phenotypically female patient initially presented with mild developmental delay and dysmorphisms. Chromosome analysis revealed a 46,XY karyotype. A 1.54 Mb microdeletion of chromosome 9q33.3 including NR5A1 was detected by array CGH and confirmed by FISH. Normal maternal FISH results indicated that this was most likely a de novo event. Since most NR5A1 mutations have been ascertained through gonadal or adrenal abnormalities, the additional findings of developmental delay and minor facial dysmorphisms are possibly related to haploinsufficiency of other genes within the 1.54 Mb deleted region. This report further confirms the role of NR5A1 deletions in 46,XY DSD and reinforces the utility of aCGH in the work up of DSDs of unclear etiology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A charitable surgical relief organization (Smile Train) enables local physicians in developing countries to provide surgical treatment of cleft lip and/or palate. The following study reviews the ...epidemiological data from more than 260,000 surgeries performed in India through this organization from 2000 until January 1, 2012.
Demographic and clinical patient data were collected from the participating surgeons, recorded in Excel (Microsoft, Redmond, WA), and analyzed using Software Package for the Social Sciences (IBM, Armonk, NY).
The distribution of clefts treated was 20.2% of cleft lip, 13.9% of cleft palate (CP), and 65.9% of cleft lip and palate. The overall unilateral-bilateral ratio was 2.49:1 with a left-right ratio of 2.03:1. The male-female ratio was 1.58:1. Of the total patients, 2.67% had associated anomalies. The most frequently performed surgeries included primary repair of a unilateral cleft lip (41.62%), followed by primary repair of a CP (31.15%). The mean age at surgery was 7.91 years. The reported complication rate was 0.88%.
The data collected are from the largest reported cohort of orofacial cleft patients in India. The cleft type, sex distribution, and overall male predominance resemble previously reported distributions; however, fewer CP patients and greater cleft lip and palate patients presented than would be expected. The frequency of associated anomalies was lower than in previous reports. Although there is significant selection bias to milder cases from lower socioeconomic groups in this study, the large sample size is unique, and the data collected can provide a valuable framework to further study the epidemiology of cleft lip and/or palate in India.
Abstract The chromosome 22q11.2 region is commonly involved in non-allelic homologous recombination (NAHR) events. Microduplications of 22q11.2, usually involving a 3 Mb or 1.5 Mb region constitute ...the 22q11 microduplication syndrome. Both microdeletions and microduplications of 22q11.21 are reported to share several phenotypic characteristics, including dysmorphic facial features, velopharyngeal insufficiency, congenital heart disease, urogenital abnormalities, and immunologic defects. We report a child who presented at 8 months of age for evaluation of microcephaly and mild motor delay. Head circumference at birth, at 8 months, and at 19 months of age was below the 3rd centile. Other findings included left-sided cryptorchidism and developmental dysplasia of the left hip. In addition, echocardiography revealed a restrictive patent ductus arteriosus. Chromosomal microarray analysis using Affymetrix Genome-Wide Human SNP Array 6.0 revealed a novel 437 kb interstitial duplication at 22q11.21, involving TBX1 , whose breakpoints did not coincide with known low copy repeat (LCR) regions. The same duplication was confirmed by fluorescent in situ hybridization (FISH) in the patient's mother and an older sister. The mother has a history of anxiety disorder and depression. The sister had a history of delayed motor milestones. None of the three duplication carriers has any documented renal anomalies or other significant medical problems. This report demonstrates the clinical heterogeneity associated with microduplications of 22q11.2 and illustrates the difficulties related to providing prognostic information and accurate genetic counseling to families when this finding is detected. The described microduplication is the smallest in this genomic region reported to date and further implicates abnormal gene dosage of TBX1 in disorders resulting from 22q11.2 rearrangements.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Infantile systemic hyalinosis (ISH) is a rare autosomal recessive disorder and an allelic form of hyaline fibromatosis syndrome that is caused by mutations in the
gene encoding the transmembrane ...anthrax toxin receptor 2. Its main features include characteristic skin lesions, joint contractures, persistent diarrhea, and failure to thrive due to accumulation of hyaline material in multiple organs. The resulting severe malnutrition can cause death in early infancy. Because of its rarity and high fatality rate, timely diagnosis is difficult and ISH may be underdiagnosed. In this report, we describe a 10-month-old male with severe protein-losing enteropathy, skin lesions, and painful joint contractures, diagnosed with ISH based on skin his-topathology and identification of a novel homozygous
mutation, c.1127_1128delTG (p.V376Gfs*14). While its clinical outcome is poor without curative treatment, establishing a diagnosis of ISH starting from clinical suspicion to molecular analysis is important for appropriate medical management and for risk and carrier assessment of family members.
Mutations in LYST, a gene encoding a putative lysosomal trafficking protein, cause Chédiak-Higashi syndrome (CHS), an autosomal recessive disorder typically characterized by infantile-onset ...hemophagocytic syndrome and immunodeficiency, and oculocutaneous albinism. A small number of reports of rare, attenuated forms of CHS exist, with affected individuals exhibiting progressive neurodegenerative disease beginning in early adulthood with cognitive decline, parkinsonism, features of spinocerebellar degeneration, and peripheral neuropathy, as well as subtle pigmentary abnormalities and subclinical or absent immune dysfunction.
In a consanguineous Pakistani kindred with clinical phenotypes consistent with attenuated CHS, we performed SNP array-based homozygosity mapping and whole gene sequencing of LYST.
We identified three individuals homozygous for a novel six base pair in-frame deletion in LYST (c.9827_9832ATACAA), predicting the loss of asparagine and threonine residues from the LYST transcript (p.Asn3276_Thr3277del), and segregating with the phenotype in this family.
We further characterize the neurologic features of the attenuated form of CHS, and discuss pathophysiologic mechanisms underlying the neurodegenerative components of CHS. Attenuated CHS is phenotypically heterogenous and should be considered when young adults develop neurodegenerative disease and have pigmentary abnormalities. We briefly discuss surveillance and management of patients with CHS-related neurodegeneration.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Pheochromocytomas are complex tumors that require a comprehensive and systematic management plan orchestrated by a multidisciplinary team.
To achieve these ends, The Mount Sinai Adrenal Center hosted ...an interdisciplinary retreat where experts in adrenal disorders assembled with the aim of developing a clinical pathway for the management of pheochromocytomas.
The result was a consensus for the diagnosis, perioperative management, and postoperative management of pheochromocytomas, with specific recommendations from our team of adrenal experts, as well as a review of the current literature.
Our clinical pathway can be applied by other institutions directly or may serve as a guide for institution-specific management.
Summary Deletions of the long arm of chromosome 4 (4q) are rare, with an estimated incidence of roughly 1 in 10,000 live births. Patients present with a constellation of findings, including cardiac ...malformations, micrognathia in the setting of Pierre Robin sequence, microcephaly, genitourinary anomalies, short stature, anomalies of the small fingers of the hand, moderate or severe learning disability, and/or severe psychomotor retardation2–4 The dysmorphic features include hypertelorism, a broad nasal bridge, with a short nose and anteverted nares, a long philtrum, a thin upper lip, and micrognathia. The cardiopulmonary complications, including asphyxia and apnea contribute significantly to morbidity and mortality. The authors describe a patient with 4q deletion syndrome and respiratory difficulty, secondary to Robin sequence. They report the successful use of distraction osteogenesis to address the associated micrognathia and tongue displacement and avoid long-term tracheostomy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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